Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2XJIOG)

• DOT Name: ATP-binding cassette sub-family G member 4 (ABCG4)
• Synonyms: EC 7.6.2.-
• Gene Name: ABCG4
• Related Disease:
  Adenocarcinoma
  Alzheimer disease
  Amyloidosis
  Brain disease
  Dementia
  Epilepsy
  Immunodeficiency
  Malaria
  Multiple sclerosis
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Syphilis
• UniProt ID: ABCG4_HUMAN
• EC Number: 7.6.2.-
• Pfam ID: PF01061 ; PF19055 ; PF00005
• Sequence:
  MAEKALEAVGCGLGPGAVAMAVTLEDGAEPPVLTTHLKKVENHITEAQRFSHLPKRSAVD
  IEFVELSYSVREGPCWRKRGYKTLLKCLSGKFCRRELIGIMGPSGAGKSTFMNILAGYRE
  SGMKGQILVNGRPRELRTFRKMSCYIMQDDMLLPHLTVLEAMMVSANLKLSEKQEVKKEL
  VTEILTALGLMSCSHTRTALLSGGQRKRLAIALELVNNPPVMFFDEPTSGLDSASCFQVV
  SLMKSLAQGGRTIICTIHQPSAKLFEMFDKLYILSQGQCIFKGVVTNLIPYLKGLGLHCP
  TYHNPADFIIEVASGEYGDLNPMLFRAVQNGLCAMAEKKSSPEKNEVPAPCPPCPPEVDP
  IESHTFATSTLTQFCILFKRTFLSILRDTVLTHLRFMSHVVIGVLIGLLYLHIGDDASKV
  FNNTGCLFFSMLFLMFAALMPTVLTFPLEMAVFMREHLNYWYSLKAYYLAKTMADVPFQV
  VCPVVYCSIVYWMTGQPAETSRFLLFSALATATALVAQSLGLLIGAASNSLQVATFVGPV
  TAIPVLLFSGFFVSFKTIPTYLQWSSYLSYVRYGFEGVILTIYGMERGDLTCLEERCPFR
  EPQSILRALDVEDAKLYMDFLVLGIFFLALRLLAYLVLRYRVKSER
• Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that may be involved in the cellular efflux of sterols, in particular cholesterol and desmosterol (a cholesterol precursor), to high-density lipoprotein (HDL). May play an important role in the removal of amyloid-beta peptides from brain, in a process that can be antagonized by desmosterol. However it is unclear whether ABCG4 can directly transport amyloid-beta peptides or whether peptide export may be facilitated due to changes in the membrane lipid environment. Induces apoptosis in various cells.
• Tissue Specificity: Expressed specifically in the brain and the eye.
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway: ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[3]
Brain disease	DIS6ZC3X	Strong	Biomarker	[4]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[5]
Malaria	DISQ9Y50	Strong	Genetic Variation	[6]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Syphilis	DISJ73BS	Strong	Biomarker	[8]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ATP-binding cassette sub-family G member 4 (ABCG4).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATP-binding cassette sub-family G member 4 (ABCG4).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of ATP-binding cassette sub-family G member 4 (ABCG4).	[11]
Exemestane	DM9HPW3	Approved	Exemestane increases the expression of ATP-binding cassette sub-family G member 4 (ABCG4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP-binding cassette sub-family G member 4 (ABCG4).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of ATP-binding cassette sub-family G member 4 (ABCG4).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-binding cassette sub-family G member 4 (ABCG4).	[13]

References

• [1] High ABCG4 Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin-Based Chemotherapy.PLoS One. 2015 Aug 13;10(8):e0135576. doi: 10.1371/journal.pone.0135576. eCollection 2015.
• [2] The Adaptor Protein Alix is Involved in the Interaction Between the Ubiquitin Ligase NEDD4-1 and its Targets, ABCG1 and ABCG4.Int J Mol Sci. 2019 Jun 2;20(11):2714. doi: 10.3390/ijms20112714.
• [3] ABCG1 and ABCG4 Suppress -Secretase Activity and Amyloid Production.PLoS One. 2016 May 19;11(5):e0155400. doi: 10.1371/journal.pone.0155400. eCollection 2016.
• [4] ABC Transporters in Neurological Disorders: An Important Gateway for Botanical Compounds Mediated Neuro-Therapeutics.Curr Top Med Chem. 2019;19(10):795-811. doi: 10.2174/1568026619666190412121811.
• [5] Oxidative Stress in HIV Infection and Alcohol Use: Role of Redox Signals in Modulation of Lipid Rafts and ATP-Binding Cassette Transporters.Antioxid Redox Signal. 2018 Feb 1;28(4):324-337. doi: 10.1089/ars.2016.6830.
• [6] Gene silencing through RNAi and antisense Vivo-Morpholino increases the efficacy of pyrethroids on larvae of Anopheles stephensi.Malar J. 2019 Aug 28;18(1):294. doi: 10.1186/s12936-019-2925-5.
• [7] Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization.Mol Carcinog. 2019 Jul;58(7):1118-1133. doi: 10.1002/mc.22996. Epub 2019 Mar 4.
• [8] Crystal stuctures of MglB-2 (TP0684), a topologically variant d-glucose-binding protein from Treponema pallidum, reveal a ligand-induced conformational change.Protein Sci. 2018 Apr;27(4):880-885. doi: 10.1002/pro.3373. Epub 2018 Feb 1.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.